E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10039073 |
E.1.2 | Term | Rheumatoid arthritis |
E.1.2 | System Organ Class | 10028395 - Musculoskeletal and connective tissue disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objectives of this study are to demonstrate, in patients on background MTX therapy, the superiority of 120 mg LY2127399 every 4 weeks (Q4W) (LY A) or 90 mg LY2127399 every 2 weeks (Q2W) (LY B), each after a loading dose, compared to placebo as follows:
American College of Rheumatology 20% response rates (ACR20) at Week 24
Structural progression as measured by van der Heijde modified Total Sharp Score (mTSS) at Week 52
Health Assessment Questionnaire-Disability Index (HAQ-DI) scores at Week 24.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are as follows:
• To demonstrate, in patients on background MTX therapy, the superiority of LY A or LY B compared to placebo over 52 weeks
• To evaluate structure (X-rays)
• To evaluate the safety and tolerability of LY A or LY B compared to placebo.
• To characterize the time course of change in absolute B cell counts, B cell subsets, and changes in serum Ig levels to treatment with LY2127399 versus placebo over 52 weeks.
• To characterize the population PK of LY2127399 and explore PK/ PD relationships with efficacy, safety and biomarker endpoints.
• To assess the potential development of anti LY2127399 antibodies and the impact on patient safety, efficacy, and PK of LY2127399.
Additional exploratory measures will be studied, including:
• To explore biomarkers that may be contained in serum, plasma, messenger ribonucleic acid (mRNA), and deoxyribonucleic acid (DNA) samples. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Protocol Addendum H9B-MC-BCDM(1), dated 27th September 2010.
To assess potential effects on immune function resulting from B cell activating factor (BAFF) neutralization, a vaccine substudy will be performed in RA patients participating in Study H9B-MC-BCDM (BCDM) in a subset of countries. Both placebo and LY2127399 treated patients will be immunized with tetanus toxoid containing and pneumococcal polysaccharide vaccines following 24 weeks of treatment. Serum antibody levels will be determined at 4 weeks following vaccination and at 28 weeks following vaccination.
The primary objectives of the vaccine sub-study are as follows:
∙ To evaluate, in RA patients on background methotrexate (MTX) therapy treated with LY A or LY B compared to placebo, the percentage of patients at 4 weeks post vaccination who have:
- a ≥4-fold increase in anti-tetanus immunoglobulin G (IgG) titer compared to baseline in those patients who have a baseline anti-tetanus IgG titer ≥0.1 IU/mL, OR
- an anti-tetanus IgG titer ≥0.2 IU/mL, in those patients who have a baseline anti tetanus IgG titer ≤0.1 IU/mL
∙ To evaluate, in RA patients on background MTX therapy treated with LY A or LY B compared to placebo, the percentage of patients at 4 weeks post vaccination who have:
- a ≥2-fold increase in anti-pneumococcal capsular polysaccharide IgG titer compared to baseline in those patients who have a baseline anti-pneumococcal capsular polysaccharide titer ≥4.0 mg/L, OR
- an anti-pneumococcal capsular polysaccharide IgG titer ≥6.0 mg/L, in those patients who have a baseline anti-pneumococcal capsular polysaccharide IgG titer <4.0 mg/L |
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E.3 | Principal inclusion criteria |
• Male and female patients aged ≥18 years of age with a diagnosis of moderately to severely active adult onset RA
• Diagnosis of Rheumatoid Arthritis (RA) of more than 6 months and less than 15 years
• Regular use of methotrexate (MTX) in the past 12 weeks, with the dose being stable during the past 8 weeks
• At least 8 tender and swollen joints
• At least one erosion of a hand or foot joint observed on an X-ray
• An abnormally high C-reactive protein (CRP) level or erythrocyte sedimentation rate (ESR)
• Positive for Rheumatoid Factor (RF) or Anti-cyclic citrullinated peptide (CCP) antibody
• Woman must not be pregnant, breastfeeding, or become pregnant during the study
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E.4 | Principal exclusion criteria |
• Use of unstable doses of non-steroidal inflammatory drugs (NSAIDS) in the past 6 weeks
• Steroid injection or intravenous (iv) infusion in the last 6 weeks
• Use of more than 10 mg/day of oral steroids in the last 6 weeks
• History of an inadequate response to a biologic disease-modifying anti-rheumatic drug (DMARD)
• History of a serious reaction to other biological DMARDs
• History of the use of rituximab or other B cell therapy
• Use of DMARDS other than MTX, hydroxychloroquine, or sulfasalazine within the last 8 weeks
• Use of leflunomide within the last 12 weeks (unless cholestyramine was used to speed up the elimination of leflunomide)
• Surgery on a joint or other major surgery less than 2 months ago, or plans to have joint surgery or major surgery during the study
• Active fibromyalgia, juvenile chronic arthritis, spondyloarthropathy, Crohn's disease, ulcerative colitis, psoriatic arthritis, or other systemic inflammatory condition except RA
• Cervical cancer or squamous skin cancer within the past 3 years, or other cancer within the past 5 years
• Received a live vaccine received within the past 12 weeks (for example, vaccines for measles, mumps, rubella, and chicken pox, and nasal-spray flu vaccines)
• Hepatitis or HIV
• A serious bacterial infection (for example, pneumonia or cellulitis) within 3 months or a serious bone or joint infection within 6 months
• Symptoms of herpes zoster or herpes simplex within the last month
• Active or latent tuberculosis (TB)
• Current symptoms of a serious disorder or illness
• Use of an investigational drug within the last month
• History of the use of rituximab, any other B cell targeted biotherapy, or denosumab |
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E.5 End points |
E.5.1 | Primary end point(s) |
• Percentage of patients with American College of Rheumatology 20% response (ACR20) at Week 24
• Change from baseline to Week 52 in van der Heijde modified Total Sharp Score (mTSS)
• Change from baseline to Week 24 in Health Assessment Questionnaire-Disability Index (HAQ-DI)
• Percentage of patients with American College of Rheumatology 50% (ACR50) and 70% (ACR70) response
• Change from baseline in Disease Activity Score C-Reactive Protein (DAS28-CRP)
• Percentage of patients with DAS28-Based European League Against Rheumatism (EULAR) response
• Change from baseline in Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) domain scores and summary scores
• Change from baseline in Brief Fatigue Inventory (BFI) individual items and impact score
• Change from baseline in duration of morning stiffness (minutes)
• Percentage of patients with Major Clinical Response (MCR) during 52 weeks
• Percentage of patients with change from baseline in mTSS less than or equal to 0
• Change from baseline in B cell subset counts
• Population Pharmacokinetics (PK)
• Percentage of patients developing anti-LY2127399 antibodies
• Change from baseline in Brief Pain Inventory Short Form (BPI-sf) individual items and interference scores
• Percentage of patients with structural inhibition at Week 52
• Change from baseline in mTSS
• Change from baseline in serum immunoglobulin (Ig) levels
• Change from baseline in joint space narrowing score and bone erosions score (components of mTSS)
• Mean percent improvement in ACR N
• Change from baseline in Tender Joint Count (68 joint count)
• Change from baseline in Swollen Joint Count (66 joint count)
• Change from baseline in Patient's Assessment of Pain (VAS)
• Change from baseline in Patient's Global Assessment of Disease Activity (VAS)
• Change from baseline in Physician's Global Assessment of Disease Activity (VAS)
• Change from baseline to Week 52 in HAQ-DI
• Change from baseline in absolute B cell counts
• Percentage of patients with ACR20 at Week 52
• Time to ACR20 response |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
•Percentage of patients with American College of Rheumatology 50% (ACR50) and 70% (ACR70) response
•Change from baseline in Disease Activity Score C-Reactive Protein (DAS28-CRP)
•Percentage of patients with DAS28-Based European League Against Rheumatism (EULAR) response
•Change from baseline in Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) domain scores and summary scores
•Change from baseline in Brief Fatigue Inventory (BFI) individual items and impact score
•Change from baseline in duration of morning stiffness (minutes)
•Percentage of patients with Major Clinical Response (MCR) during 52 weeks
•Percentage of patients with change from baseline in mTSS less than or equal to 0
•Change from baseline in B cell subset counts
•Population Pharmacokinetics (PK)
•Percentage of patients developing anti-LY2127399 antibodies
•Change from baseline in Brief Pain Inventory Short Form (BPI-sf) individual items and interference scores
•Percentage of patients with structural inhibition at Week 52
•Change from baseline in mTSS
•Change from baseline in serum immunoglobulin (Ig) levels
•Change from baseline in joint space narrowing score and bone erosions score (components of mTSS)
•Mean percent improvement in ACR N
•Change from baseline in Tender Joint Count (68 joint count)
•Change from baseline in Swollen Joint Count (66 joint count)
•Change from baseline in Patient's Assessment of Pain (VAS)
•Change from baseline in Patient's Global Assessment of Disease Activity (VAS)
•Change from baseline in Physician's Global Assessment of Disease Activity (VAS)
•Change from baseline to Week 52 in HAQ-DI
•Change from baseline in absolute B cell counts
•Percentage of patients with ACR20 at Week 52
•Time to ACR20 response
•Change from baseline in CRP
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Bulgaria |
Colombia |
Croatia |
Hungary |
India |
Japan |
Korea, Republic of |
Lithuania |
Malaysia |
Mexico |
New Zealand |
Peru |
Poland |
Romania |
Russian Federation |
Slovakia |
South Africa |
Sri Lanka |
Taiwan |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |